To maximize both humoral and cellular immune responses against HIV/SIV, combinations of immunogens will be administered according to the "prime- boost" concept: an initial series of immunizations with a vector capable of intracellular expression of encoded viral antigens primes the immune system and induces T-cell mediated responses, including CTL; a subsequent boost with soluble proteins stimulates B-cell responses, including neutralizing antibodies. In this project, we will develop new immunogens suitable for the priming phase, based on both modified vaccinia Ankara (MVP) and DNA constructs, and test them for immunogenicity in macaques. We will also evaluate in guinea pigs and macaques multiple different designs for soluble proteins boosts, including pseudovirions and various forms of monomeric and oligomeric envelop glycoproteins. The most promising priming and boosting components will be combined and further evaluated in macaques, culminating in assessment of their ability to protect the animals from infection with SHIV's containing the env of subtype C HIV-1 strains. Four specific aims are proposed: 1. Construction of recombinant vaccinia viruses and pseudovirions. 2. Construction of DNA vaccines. 3. Testing of immunogens, adjuvants and liposomes in vitro and in animals. 4. Testing of the prime-boost strategy for immunogenicity and SHIV protection in macaques.